Goulielmaki, Evi, Ioannidou, Anna, Tsekrekou, Maria ORCID: 0000-0002-0635-1499, Stratigi, Kalliopi, Poutakidou, Ioanna K., Gkirtzimanaki, Katerina, Aivaliotis, Michalis ORCID: 0000-0003-1173-7705, Evangelou, Konstantinos, Topalis, Pantelis, Altmueller, Janine, Gorgoulis, Vassilis G., Chatzinikolaou, Georgia and Garinis, George A. ORCID: 0000-0002-3200-5004 (2020). Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1(F/-)) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1(F/-) animal sera and are secreted in macrophage media after DNA damage. The Er1(F/-) EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Goulielmaki, EviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ioannidou, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsekrekou, MariaUNSPECIFIEDorcid.org/0000-0002-0635-1499UNSPECIFIED
Stratigi, KalliopiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poutakidou, Ioanna K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gkirtzimanaki, KaterinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aivaliotis, MichalisUNSPECIFIEDorcid.org/0000-0003-1173-7705UNSPECIFIED
Evangelou, KonstantinosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Topalis, PantelisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorgoulis, Vassilis G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chatzinikolaou, GeorgiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garinis, George A.UNSPECIFIEDorcid.org/0000-0002-3200-5004UNSPECIFIED
URN: urn:nbn:de:hbz:38-349255
DOI: 10.1038/s41467-019-13894-9
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NUCLEOTIDE EXCISION-REPAIR; NF-KAPPA-B; GLUCOSE-TRANSPORT; STATISTICAL-MODEL; IN-VIVO; PROTEINS; OBESITY; MICE; ERCC1-XPF; LONGEVITYMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34925

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